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. 2023 Aug:70:82-91.
doi: 10.1016/j.breast.2023.06.005. Epub 2023 Jun 27.

Concordance of HER2-low scoring in breast carcinoma among expert pathologists in the United Kingdom and the republic of Ireland -on behalf of the UK national coordinating committee for breast pathology

Mohamed Zaakouk  1 , Cecily Quinn  2 , Elena Provenzano  3 , Clinton Boyd  4 , Grace Callagy  5 , Soha Elsheikh  6 , Joe Flint  7 , Rebecca Millican-Slater  8 , Anu Gunavardhan  9 , Yasmeen Mir  10 , Purnima Makhija  11 , Silvana Di Palma  12 , Susan Pritchard  13 , Bruce Tanchel  14 , Emad Rakha  15 , Nehal M Atallah  16 , Andrew H S Lee  15 , Sarah Pinder  17 , Abeer M Shaaban  18
Affiliations

Concordance of HER2-low scoring in breast carcinoma among expert pathologists in the United Kingdom and the republic of Ireland -on behalf of the UK national coordinating committee for breast pathology

Mohamed Zaakouk et al. Breast. 2023 Aug.

Abstract

Background: Recent clinical evidence showed that breast cancer with low HER2 expression levels responded to trastuzumab deruxtecan therapy. The HER2-low cancers comprise immunohistochemistry (IHC) score 1+ and 2+ ISH non-amplified tumours, currently classified as HER2 negative. Little data exists on the reproducibility of pathologists reporting of HER2-low cancer.

Patient and methods: Sixteen expert pathologists of the UK National Coordinating Committee for Breast Pathology scored 50 digitally scanned HER2 IHC slides. The overall level of agreement, Fleiss multiple-rater kappa statistics and Cohen's Kappa were calculated. Cases with low concordance were re-scored by the same pathologists after a washout period.

Results: Absolute agreement was achieved in 6% of cases, all of which scored 3+. Poor agreement was found in 5/50 (10%) of cases. This was due to heterogeneous HER2 expression, cytoplasmic staining and low expression spanning the 10% cut-off value. Highest concordance (86%) was achieved when scores were clustered as 0 versus others. Improvement in kappa of overall agreement was achieved when scores 1+ and 2+ were combined. Inter-observer agreement was moderate to substantial in the whole cohort but fair to moderate in the HER2-low group. Similarly, consensus-observer agreement was substantial to almost perfect in the whole cohort and moderate to substantial in the HER2-low group.

Conclusion: HER2-low breast cancer suffers from lower concordance among expert pathologists. While most cases can reproducibly be classified, a small proportion (10%) remained challenging. Refining the criteria for reporting and consensus scoring will help select appropriate patients for targeted therapy.

Keywords: Breast cancer; Concordance; Consistency; HER2-Low; HER2-Ultralow; Immunohistochemistry.

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Conflict of interest statement

Declaration of competing interest EP has received honoraria from Roche, Novartis and AstraZeneca for lectures and participating in advisory committees. SP has received honoraria as speaker and advisory board member for Exact Sciences. AMS has received honoraria as speaker and advisory board member for Exact Sciences, Veracyte, Roche, Hologic, Diaceutics and AstraZeneca.

Figures

Fig. 1
Fig. 1
Flow chart of the study design.
Fig. 2a
Fig. 2a
Examples of HER2 immunohistochemical staining and interpretation in the studied cohort. A. Breast carcinoma showing absolute (100%) agreement on scoring of 3+. B, C. Two fields of challenging case 4 with a consensus score of 1+ (HER2-low).
Fig. 2b
Fig. 2b
D. Challenging case 5 showing faint membranous staining and background staining making it difficult to assess. Consensus was 0 in round 1 and 1+ in round 2.
Fig. 2c
Fig. 2c
E. Low power overview of breast carcinoma cores showing clustered heterogeneous expression of HER2. Consensus score was 2+.
Fig. 2d
Fig. 2d
F. high power view of the same case showing a clone with strong complete membranous staining.
See this image and copyright information in PMC

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